Publication Date
2024
Document Type
Thesis
Committee Members
Andrew Voss, Ph.D. (Advisor); Hongmei Ren, Ph.D. (Committee Member); David Ladle, Ph.D. (Committee Member)
Degree Name
Master of Science (MS)
Abstract
One of the less studied aspects of Huntington’s disease (HD) is its impact on skeletal muscle function. Recent studies have suggested that HD patients exhibit altered muscle function and reduced muscle strength, which may be related to defects in Ca2+ handling during excitation-contraction coupling (ECC). However, the underlying mechanisms of these alterations remain poorly understood. This study aims to determine if the myoplasmic Ca2+ during ECC is reduced in late-stage R6/2 (mouse model of HD) muscle fibers compared to age-matched controls during twitch or tetanic stimulation. Such a decrease would help explain weakness or fatigue in the model HD muscle. Previous work from our lab and other groups has measured a decreased rate of Ca2+ release from the sarcoplasmic reticulum (SR) during ECC. We have also shown that action potentials are prolonged in R6/2 skeletal muscle. Our previous work did not assess Ca2+ reuptake into the SR, in part because of the high concentration of EGTA, a Ca2+ chelator, equilibrated into the muscle via intracellular electrodes. Another group assessed Ca2+ release and reuptake using optical methods under a limited range of conditions with extensive modeling. For this project, we used optical methods to measure Ca2+ levels in isolated R6/2 and control muscle during various stimulation protocols in the absence of EGTA. Additionally, we quantified the amounts of key proteins involved in Ca2+ handling, including sarco/endoplasmic reticulum Ca2+ -ATPase (SERCA), troponin C, and parvalbumin, in HD muscle cells using Western blot techniques. Overall, the objective of this study was to provide a more complete measure of muscle Ca2+ during ECC that can be used to build a predictive model of Ca2+ homeostasis in active R6/2 and control skeletal muscle. This study improves our understanding of the mechanisms underlying muscle dysfunction in HD. Ultimately, this study may lead to the development of new treatments to improve muscle function in HD patients.
Page Count
76
Department or Program
Department of Biological Sciences
Year Degree Awarded
2024
Copyright
Copyright 2024, all rights reserved. My ETD will be available under the "Fair Use" terms of copyright law.
